Manipulating Protein Acetylation in Breast Cancer: A Promising Approach in Combination with Hormonal Therapies?

Estrogens play an essential role in the normal physiology of the breast as well as in mammary tumorigenesis. Their effects are mediated by two nuclear estrogen receptors, ERα and β, which regulate transcription of specific genes by interacting with multiprotein complexes, including histone deacetylases (HDACs). During the past few years, HDACs have raised great interest as therapeutic targets in the field of cancer therapy. In breast cancer, several experimental arguments suggest that HDACs are involved at multiple levels in mammary tumorigenesis: their expression is deregulated in breast tumors; they interfere with ER signaling in intricate ways, restoring hormone sensitivity in models of estrogen resistance, and they clinically represent new potential targets for HDACs inhibitors (HDIs) in combination with hormonal therapies. In this paper, we will describe these different aspects and underline the clinical interest of HDIs in the context of breast cancer resistance to hormone therapies (HTs)

Sacituzumab govitecan as second-line treatment for metastatic triple-negative breast cancer—phase 3 ASCENT study subanalysis

Breast cancer; Second-line treatmentCáncer de mama; Tratamiento de segunda líneaCàncer de mama; Tractament de segona líniaPatients with triple-negative breast cancer (TNBC) who relapse early after (neo)adjuvant chemotherapy have more aggressive disease. In the ASCENT trial, sacituzumab govitecan (SG), an antibody-drug conjugate composed of an anti-Trop–2 antibody coupled to SN-38 via a hydrolyzable linker, improved outcomes over single-agent chemotherapy of physician’s choice (TPC) in metastatic TNBC (mTNBC). Of 468 patients without known baseline brain metastases, 33/235 vs 32/233 patients (both 14%) in the SG vs TPC arms, respectively, received one line of therapy in the metastatic setting and experienced disease recurrence ≤12 months after (neo)adjuvant chemotherapy. SG prolonged progression-free survival (median 5.7 vs 1.5 months [HR, 0.41; 95% CI, 0.22–0.76]) and overall survival (median 10.9 vs 4.9 months [HR, 0.51; 95% CI, 0.28–0.91]) vs TPC, with a manageable safety profile in this subgroup consistent with the overall population. In this second-line setting, as with later-line therapy, SG improved survival over conventional chemotherapy for patients with mTNBC.This study was sponsored by Gilead Sciences, Inc

Palbociclib with Fulvestrant or Letrozole in Endocrine-Sensitive Patients with HR-Positive/HER2-Negative Advanced Breast Cancer: A Detailed Safety Analysis of the Randomized PARSIFAL Trial

Endocrine therapy; Neutropenia; Venous thromboembolismTerapia endocrina; Neutropenia; Tromboembolismo venosoTeràpia endocrina; Neutropènia; Tromboembolisme venósBackground Palbociclib has gained a central role in the treatment of hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer (ABC). Despite its manageable toxicity profile, venous thromboembolism (VTE) or interstitial lung disease (ILD)/pneumonitis may infrequently occur. Therefore, we provide a comprehensive summary of the safety and tolerability of the combination of endocrine therapy and palbociclib among patients included in the randomized phase 2 PARSIFAL study. Materials and Methods Patients with endocrine-sensitive HR+/HER2- ABC and no prior therapy in an advanced setting (n = 486) were randomly assigned 1:1 to receive fulvestrant–palbociclib (FP) or letrozole–palbociclib (LP). Laboratory tests and the incidence of adverse events (AEs) were recorded at baseline and day 1 of each cycle. Progression-free survival (PFS) was estimated for patients with and without VTE. Results A total of 483 patients were analyzed. Neutropenia, leukopenia, anemia, asthenia, arthralgia, fatigue, and diarrhea were the most frequent AEs in both groups. Febrile neutropenia occurred in 3 (1.2%) patients of the FP group and in 1 (0.4%) patient in the LP group. Six (2.5%; 0.4% grade 3) patients in the FP group and 6 patients (2.5%; 0.4% grade 3) in the LP group experienced ILD/pneumonitis. Pulmonary embolism was reported in 12 (5.0%) patients in the FP group and 6 (2.5%) patients in the LP group. Advanced age at baseline was the only factor significantly associated with an increased risk of pulmonary embolism (P < .01). Conclusion The PARSIFAL data confirmed the favorable safety profile of both palbociclib regimens. VTE and ILD/pneumonitis were occasionally reported, and their early detection allowed patients to continue treatment effectively without detriment to efficacy.The PARSIFAL study was sponsored by Medica Scientia Innovation Research S.L. (MEDSIR) and funded by Pfizer, who had no role in the design and conduct of this study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Fulvestrant was provided by AstraZeneca

Severe toxic rhabdomyolysis under combined palbociclib and simvastatin treatment: A case report

We report the fourth described case of severe toxic rhabdomyolysis occurring in an 81-year-old woman caused by the concomitant administration of palbociclib taken at the usual dosage (125 mg per day) and simvastatin. To the best of our knowledge, this is the first reported case successfully treated by plasma exchanges, with complete functional recovery within two months. The severity of this case justifies further consideration of pharmacokinetic interactions between palbociclib or other CDK-4-6 inhibitors and statins, which potentially increase the risk of an adverse event

Incidence of reversible amenorrhea in women with breast cancer undergoing adjuvant anthracycline-based chemotherapy with or without docetaxel

<p>Abstract</p> <p>Background</p> <p>To determine the incidence of reversible amenorrhea in women with breast cancer undergoing adjuvant anthracycline-based chemotherapy with or without docetaxel.</p> <p>Methods</p> <p>We studied the incidence and duration of amenorrhea induced by two chemotherapy regimens: (i) 6 cycles of 5-fluorouracil 500 mg/m², epirubicin 100 mg/m²and cyclophosphamide 500 mg/m²on day 1 every 3 weeks (6FEC) and (ii) 3 cycles of FEC 100 followed by 3 cycles of docetaxel 100 mg/m²on day 1 every 3 weeks (3FEC/3D). Reversible amenorrhea was defined as recovery of regular menses and, where available (101 patients), premenopausal hormone values (luteinizing hormone (LH), follicle-stimulating hormone (FSH) and estradiol) in the year following the end of chemotherapy.</p> <p>Results</p> <p>One hundred and fifty-four premenopausal patients were included: 84 treated with 6FEC and 70 with 3FEC/3D. The median age was 43.5 years (range: 28–58) in the 6FEC arm and 44 years (range: 29–53) in the 3FEC/3D arm. Seventy-eight percent of patients were treated in the context of the PACS 01 trial. The incidence of chemotherapy-induced amenorrhea at the end of chemotherapy was similar in the two groups: 93 % in the 6FEC arm and 92.8 % in the 3FEC/3D arm. However, in the year following the end of chemotherapy, more patients recovered menses in the 3FEC/3D arm than in the 6FEC arm: 35.5 % versus 23.7 % (p = 0.019). Among the 101 patients for whom hormone values were available, 43 % in the 3FEC/3D arm and 29 % in the 6FEC arm showed premenopausal levels one year after the end of chemotherapy (p < 0.01). In the 3FEC/3D group, there was a statistically significant advantage in disease-free survival (DFS) for patients who were still amenorrheic after one year, compared to patients who had recovered regular menses (p = 0.0017).</p> <p>Conclusion</p> <p>Our study suggests that 3FEC/3D treatment induces more reversible amenorrhea than 6FEC. The clinical relevance of these findings needs to be investigated further.</p

La chirurgie après chimiothérapie néoadjuvante pour cancer du sein opérable d'emblée (étude rétrospective de 201 cas pris en charge en 6 ans à l'Institut Claudius Régaud)

Cette étude rétrospective porte sur 201 patientes traitées à l'Institut Claudius Regaud, entre Janvier 2002 et Décembre 2007, par chimiothérapie néoadjuvante, dans le cadre d'un carcinome mammaire ne permettant pas une chirurgie conservatrice d'emblée. La série retrouve des résultats comparables à ceux de la littérature, avec un taux de conservation mammaire de 59% au final, après une reprise chirurgicale de 14,5% des patientes pour marges insuffisantes. Le taux de rechute locale à 4 ans est alors de 4,5%. Dans 20,8% des cas une réponse histologique complète à la fois tumorale et ganglionnaire a été obtenue. En cas de réponse partielle le mode de régression tumorale était centripète dans 37,9% des cas et éclaté pour les 62,1% restants. Une amélioration de l'évaluation du résidu tumoral par l'imagerie avec le temps a été notée, notamment avec l'introduction de l'IRM systématique.TOULOUSE3-BU Santé-Centrale (315552105) / SudocSudocFranceF

Carcinome du sein inflammatoire non métastatique (l'évolution des traitements et le rôle de la dose-intensité de chimiothérapie revus à propos d'une série de 157 cas en 20 ans a l'Institut Claudius Regaud)

TOULOUSE3-BU Santé-Centrale (315552105) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF